Infectious diseases cause a tremendous burden of morbidity and mortality worldwide. In order to mitigate the disease burden arising from infectious microbes, it is critical to have a comprehensive understanding of the entire repertoire of host defenses against microbial infection. Our current understanding of antiviral host defense mechanisms encompasses a wide range of branches and effector mechanisms, including adaptive pathways based on antibody and T-cell responses and innate immune mechanisms, such as interferon mediated signaling. However, this is unlikely to be the complete picture of all antiviral responses. The fact that it has only been in the past decade or so that fundamental innate immune pathways, such as RNA interference (RNAi) and signaling by Toll-like receptors (TLRs), were discovered reflects how much remains to be discovered about the immune system and raises the distinct possibility that additional innate pathways may exist that remain undiscovered today. Model organisms have proven invaluable in defining biological processes central to human biology. For example, antimicrobial functions of TLRs were first identified in studies of Drosophila, and the seminal studies of RNA interference (RNAi) were performed in C. elegans. However, the C. elegans model has been largely ignored in the studies of host-viral immunity. The paucity of efforts to apply C. elegans to define antiviral host responses stems directly from the complete absence of viruses capable of infecting C. elegans. With our recent discovery of the first viruses capable of infecting Caenorhabditis nematodes and the establishment of a bona fide experimental viral infection system, it is now possible for the first time to explore physiologically relevant host responses to natural viral infection in this genetically tractable model organism. This proposal aims (1) to generate the first data defining the host transcriptional response to viral infection in both C. briggsae and C. elegans and thereby identify a consensus set of genes that respond to viral infection of nematodes and (2) to identify antiviral genes by depleting genes that are part of the consensus transcriptional response cassette defined in Aim 1. These studies will provide the first insights into the transcriptional networks induced by viral infection, and have the potential to define genes that play antiviral roles in nematodes that may also be evolutionarily conserved in humans or mammals.